The present invention concerns heterocyclic carbon compounds comprising 4-phenyl-1,4-dihydropyridines with a piperazinyl- or homopiperazinyl-containing moiety attached to the 3-position of the 4-phenyl ring. These compounds act as NPY antagonists. As such they should represent a class of improved anorexiants lacking some of the side-effects possessed by currently available anorexiants.
A substantial body of art has accumulated over the past two decades with respect to 4-aryl-1,4-dihydropyridine compounds. A large number of these possess calcium antagonist properties and find utility in the treatment of cardiovascular diseases.
Earlier work from these laboratories involved a series of 4-aryl-dihydropyridine cardiovascular agents, including compounds of formula (1), which were ##STR2## disclosed and claimed in U.S. Pat. No. 4,755,512.
Additionally, 1,4-dihydropyridine compounds have been disclosed that have an arylpiperazine system attached by an alkyl or alkoxyalkyl chain to the R.sup.2 -position of the dihydropyridine ring. Aritomi, et al., in Chem. Pharm. Bull., 28 (11), 3163-71 (1980) disclose compounds having an alkylenylpiperazine group at the 2-position of the dihydropyridine nucleus, e.g. ##STR3## wherein n=2 and R is alkyl, aryl, or arylalkyl. Specifically disclosed is compound (2). ##STR4##
European Patent Application 60,674, published in 1982, discloses anti-ischemic and antihypertensive agents of structure (3) ##STR5## wherein Y is an ethylene or propylene chain; R.sup.5 is C.sub.1-4 alkyl, aryl, arylalkyl, and the like.
These reference compounds are easily distinguished structurally from the compounds of the instant invention by virtue of being attached to the dihydropyridine ring as well as by the nature of the linking functional group, e.g. alkylenyl, alkylene-oxo-alkylenyl, and carboxamido groups. In contrast, compounds of the instant invention contain an alkylenylpiperazine moiety attached to the 4-phenyl ring by means of an urea or anilide connection. Not only are the present compounds structurally novel, they also have been discovered to possess novel NPY antagonist activity.
Neuropeptide Y (NPY) is a 36 amino acid peptide first isolated in 1982 from porcine brain..sup.1,2 The peptide is a member of a larger peptide family which also includes peptide YY (PYY), pancreatic peptide (PP), and the non-mammalian fish pancreatic peptide Y (PY). Neuropeptide Y is very highly conserved in a variety of animal, reptile and fish species. It is found in many central and peripheral sympathetic neurons and is the most abundant peptide observed in the mammalian brain. In the brain, NPY is found most abundantly in limbic regions. The peptide has been found to elicit a number of physiological responses including appetite stimulation, anxiolysis, hypertension, and the regulation of coronary tone.
Structure-activity studies with a variety of peptide analogs (fragments, alanine replacements, point mutations, and internal deletion/cyclized derivatives) suggest a number of receptor subtypes exist for NPY..sup.2b These currently include the Y.sub.1, Y.sub.2, Y.sub.3, and the Y.sub.1-like or Y.sub.4 subtypes.
Although a number of specific peptidic antagonists have been identified for most of the subtypes, few selective non-peptidic antagonists have been reported to date. Examples of these antagonists are displayed in Charts 1 and 2. The heterocyclic guanidine derivative He 90481 (4) was found to be a weak but competitive antagonist of NPY-induced Ca.sup.++ entry in HEL cells (pA.sub.2 =4.43)..sup.3 The compound was also found to have .alpha..sub.2 -adrenergic and histaminergic activity at this dose range. D-Myo-inositol-1,2,6-triphosphate (5) was reported to be a potent but non-competitive antagonist to NPY-induced contractions in guinea pig basilar artery..sup.4 Similarly, the benextramine-like bisguanidines 6a and 6b were reported to displace .sup.3 H-NPY in rat brain (IC.sub.50, 19 and 18.4 .mu.M) and to display functional antagonism in rat femoral artery..sup.5 The bisguanidine 6b was shown to be functionally selective for the Y.sub.2 receptor since it antagonized the effect of the NPY.sub.2 agonist NPY.sub.13-36 but had no effect on the vasoconstrictive activity of the NPY.sub.1 agonist [Leu.sup.31, Pro.sup.34 ]NPY..sup.5c
Compound (7), BIBP 3226.sup.6, displaces I-125 Bolton-Hunter labeled NPY in human neuroblastoma cells (SK-N-MC). Compound (7) antagonized the NPY-induced increase in intracellular Ca.sup.++ in SK-N-MC cells as well as antagonizing the NPY-induced pressor response in pithed rat experiments.
In addition to displacing I-125 labeled NPY and PYY in human neuroblastoma cells, compound (8), SR 120819A.sup.7, also antagonized NPY-related increases in diastolic blood pressure in an anesthetized guinea pig model.
In sum, the compounds of this invention may be distinguished over compounds of the prior art on the basis of molecular structure and biologic activity. There is nothing in the prior art that anticipates or suggests the novel NPY antagonists of the present invention.